1. Field of the Invention
The present invention relates to Tc-labeled arylpiperazine derivatives for imaging serotonin receptor, and more particularly, to arylpiperazine derivatives coupled with MAMA-disulfide, N2S2 or dimethyl-N2S2 chelating ligand, which is useful for imaging cranial nervous system.
2. Description of Prior Art
Transmission of nerve impulses and functions of vital organs are controlled by neurotransmitters. A neurotransmitter system includes cholinergic nervous system releasing acetylcholine and adrenergic nervous system releasing noradrenaline. Acetylcholine and noradrenaline are released by stimulation in central and peripheral nervous systems.
Additionally, in the central nervous system, there are many important neurotransmitters such as dopamine, serotonin and inhibitory GABA (γ-aminobutyric acid). Among them, serotonergic nervous system is closely related to mental illness such as anxiety, worry and melanocholia. It is known that the distribution of serotonin receptors is remarkably reduced in patients with schizophrenia or dementia. The serotonergic system in the brain is an important neurotransmitter system that controls actions including worry and emotional anxiety, and physical functions.
It is also known that the serotonergic system having various receptor subtypes is a very important neurotransmitter system in the brain and is involved in the regulation of various physiological functions and mental state.
Serotonin receptors activated by 5-HT have been divided into at least seven classes (5-HT1-7), and each class has been further subdivided into different subtypes (A, B, . . . ). 5-HT1A, which is one of the serotonin receptor subtypes, functions as a somatodendritic autoreceptor (presynaptic) in the dorsal raphe nucleus and as a postsynaptic receptor for 5-HT in terminal field areas.
Numerous research studies on agonists and antagonists for 5-HT1A receptors have been extensively conducted and excellent compounds were obtained. WAY100635, which is an arylpiperazine compound, is known as a typical antagonist. It was identified that WAY100635 is an important ligand for imaging 5-HT1A receptor.
The antagonists are important ligands for imaging 5-HT1A receptor. Radioactive ligands (radioligands) are obtained by labeling antagonists with radioactive isotopes such as carbon-11, fluorine-18 and iodine-125, etc.
A radioactive ligand of WAY100635 is synthesized by labeling carbon of methoxy or carbonyl group of WAY100635 with carbon-11. Central 5-HT1A receptors in the human brain are imaged by positron emission tomography (PET) using the radioligand.
The radioligand meets almost all requirements. However, it has a disadvantage that it is metabolized by amide hydrolysis in the human liver. It has another disadvantage that isotopes such as carbon-11 (halflife=20 min.) and fluorine-18 (halflife=2 hrs) have to be synthesized at cyclotron, and their halflives are too short, thereby resulting in limitation in the application thereof.
It has further disadvantages that iodine-125 has to be prepared one by one and it has to be applied only for animals because its halflife is too long.
Therefore, the development of new compounds that have a high affinity for 5-HT1A without problem of amide hydrolysis and is labeled with technetium (Tc) having radiochemically optimum conditions (easy manufacturability, halflife, radioactive level, easy purchase), without labeling of arylpiperazine compounds with carbon-11 or fluorine-18, is required.
In the other hand, a method of synthesizing WAY100635 derivatives by a conventional heat treatment had many problems that a large amount of solvent is required, reaction time is long and yield is low.
As a method to solve these problems, green chemistry began to draw attention recently and organic synthesis, which can reduce by-products, waste production and energy cost, is highlighted. An example of the organic synthesis is microwave irradiation (MWI) that induces direct coupling between reaction molecules and shows thermal conductivity leading to rapid rise in reaction temperature. MWI has outstanding advantages of shorter reaction time, higher yield, easier work-up and cleaner reaction due to less side reactions than organic synthesis according to a conventional heating.
The inventors have conducted numerous studies in order to solve the problems of the amide hydrolysis and of the conventional organic synthesis using heating. As a result, new arylpiperazine derivatives are synthesized by acylation of 2-aminopyridine and reduction of the arylpiperazine using microwave irradiation instead of the conventional heating method, and thiol compounds are synthesized by coupling the derivatives with N2S2 radioligand.
It was identified that the compounds have a high affinity for 5-HT1A and can be labeled with technetium that is the most useful radioactive isotope for nuclear-medicine imaging diagnosis. Based on these findings, the present invention has been completed.